Project Summary/Abstract The goals of this project are to understand the mechanistic basis for the increased incidence of diffuse large B cell lymphoma (DLBCL) associated with aging in humans. It has been known for decades that aging mice frequently develop lymphomas and work in mouse models have identified age-associated reduction in the DNA damage response (DDR). The ATM gene, a master regulator of the DNA damage-signaling pathways is responsible for ataxia-telangiectasia (AT), and is essential for maintaining the integrity of the genome. The Levine group demonstrated that the function of ATM kinase declines significantly with age in mice. Of clinical relevance, human peripheral blood lymphocytes from older individuals also demonstrate an attenuated response after exposure to genotoxic stresses. Interestingly, a significant percentage of DLBCL exhibited elevated levels of the oncogenic microRNA-421 which down-regulates levels of ATM protein. The levels of expressed genes are controlled through both transcriptional and post-transcriptional/translational events after genotoxic stress exposure. RNA-binding proteins (RBP) and microRNAs are major posttranscriptional/ translational regulators of gene expression. This synchronized regulation of mRNA subsets is the basis of the post-transcriptional RNA-operon model whereby RBPs coregulate multiple mRNAs and thereby regulate the co-expression of proteins with related function. The RBP, HuR is recognized as a key post-transcriptional regulator of mRNAs encoding proteins central to the cellular stress response. Our group recently identified those transcripts differentially associated with HuR, including multiple cancer-related mRNAs in an ATM/Chk2- dependent manner. The specific hypothesis to be investigated is that the aberrant posttranscriptional regulation of genes by HuR in response to IR contributes to lymphomagenesis in the elderly. In Specific Aim 1, we will investigate the linkage between aberrant post-transcriptional regulation of genes and aging in human B- cell lymphocytes. In Specific Aim 2, we will investigate if the oncogenic microRNA-421 contributes to DLBCL development. In Specific Aim 3, we will investigate whether the development of splenic lymphomas in aging mouse are mechanistically linked with defects in post-transcriptional gene regulation. Our proposal should provide a functional link between ATM and HuR's posttranscriptional role in mediating oncogenic, and antiapoptotic activities as well as to validat the paradigm that the age-associated decline in function of ATM underlies the increased incidence of non-Hodgkin's lymphoma (NHL) observed with increasing age.